ORIGINAL STUDY Efficacy and safety of ziv-aflibercept in patients with neovascular age-related macular degeneration in a Ghanaian population

Efficacy and safety of ziv-aflibercept in patients with neovascular age-related macular degeneration in a Ghanaian population

IZ Braimah MBChB, FGCS, FWACS; Senior lecturer and consultant ophthalmologist, Department of Surgery (Eye), University of Ghana Medical School, Korle-Bu, Accra; Lions International Eye Centre, Korle-Bu Teaching Hospital, Korle-Bu, Accra, Ghana ORCID ID: https://orcid.org/0000-0002-2573-9026

YS Adam MBBS; Consultant ophthalmologist, Lions International Eye Centre, Korle-Bu Teaching Hospital, Korle-Bu, Accra, Ghana

WM Amoaku MBChB, FRCS(Ed), FRCOphth, PhD; Associate Professor/Reader, Academic Ophthalmology, DCN, Faculty of Medicine and Health Sciences, University of Nottingham, Nottingham, UK ORCID ID: https://orcid.org/0000-0001-5028-7984

Corresponding author: Winfried M Amoaku, tel: +441158231014; email: winfried.amoaku@nottingham.ac.uk

Abstract

Background: To report on the efficacy and safety of intravitreal ziv-aflibercept (IVZ) in a Ghanaian population with neovascular age-related macular degeneration (nAMD).

Methods: In this retrospective, observational study, the medical records of patients with nAMD who had been treated with IVZ, 1.25 mg/0.05 ml, as part of routine clinical practice on pro re nata basis with a minimum follow-up of 6 months, were retrieved and analysed.

Results: Twenty-four eyes of 23 patients were included in this study. Their mean age was 67.7±8.8 yrs, and mean duration of follow-up was 11.4±4.0 months. Nine (37.5%) eyes were presumed to have polypoidal choroidal vasculopathy (PCV).

The mean baseline best-corrected visual acuity (BCVA) was 1.1±0.7 logMAR; there was significant improvement in BCVA at 3 and 6 months compared to baseline (p<0.01). Seventy-nine per cent of eyes had visual gain of at least one logMAR BCVA line at 6 months post-initiation of IVZ. The mean CMT at baseline was 332.4±138.8 μm; there was significant reduction in CMT at 3, 6 and 12 months compared to baseline (p<0.01). One case of culture-proven endophthalmitis was successfully treated with pars plana vitrectomy and intravitreal antimicrobials.

Conclusion: IVZ at 1.25 mg was associated with significant improvement in visual and anatomic outcomes in Ghanaian eyes with nAMD. There was one serious adverse event with unfavourable visual outcome.

Keywords: ziv-aflibercept, endophthalmitis, Ghana, neovascular macular degeneration, optical coherence tomography

Funding: This research received no specific grant from any funding agency in the public, commercial or not-for-profit sectors.

Conflict of interest: The authors have no conflicts of interest to declare.

Introduction

Age-related macular degeneration (AMD) is a major cause of visual impairment and blindness worldwide.1 There are significant differences in the prevalence of different types of AMD including neovascular AMD (nAMD) between different ethnic groups.2 The prevalence of early AMD is higher among people of European ancestry compared to African and Asian ancestry.2 Late AMD is more prevalent among people of European ancestry compared to African ancestry.2 Polypoidal choroidal vasculopathy (PCV), a variant of nAMD, has been found to be more prevalent among Asians and African Americans compared to Caucasians.3

Vascular endothelial growth factor (VEGF) plays an important role in the pathogenesis of nAMD.4 While ranibizumab (Lucentis, Genentech/Novartis) and aflibercept (Eylea, Regeneron/Bayer) have been approved by the United State of America (USA) Food and Drugs Agency (FDA) and European Medicines Agency (EMA) for intravitreal use in patients with nAMD, bevacizumab (Avastin, Genentech/Roche) and ziv-aflibercept (Regeneron/Sanofi) have been approved by both agencies for the treatment of colorectal cancers.5,6

The Comparison of Age-Related Macular Degeneration Treatment Trials (CATT) and Inhibition of VEGF in Age-related Choroidal Neovascularisation (IVAN) trials have reported that ranibizumab and bevacizumab have similar efficacy in patients with nAMD.7,8 The VEGF Trap-Eye: Investigation of Efficacy and Safety in Wet AMD (VIEW) 1 and 2 studies have shown that aflibercept has similar efficacy as ranibizumab in nAMD.9,10 Bevacizumab is widely used off-label for the treatment of nAMD due to its cost-effectiveness compared to ranibizumab.11 Aflibercept is expensive and beyond the reach of many patients in developing and low- to middle-income countries in the world. Ziv-aflibercept (an intravenous formulation of aflibercept) has been used off-label for the treatment of nAMD and there are few published reports of the safety and efficacy of this drug.12-15

In a randomised double blind intervention study of Ghanaian eyes with choroidoretinal vascular diseases, our group found that the short-term use of intravitreal ziv-aflibercept (IVZ) was safe.16 There is no data on the efficacy of off-label use of ziv-aflibercept in a West African population with nAMD to date. We evaluated the outcome of treatment with IVZ in a Ghanaian population with nAMD.

Materials and methods

This retrospective interventional study involved patients with nAMD who were treated with IVZ from October 2016 to February 2018 at the Eye Centre, KorleBu Teaching Hospital, Accra. The study adhered to the tenets of the Declaration of Helsinki and the study protocol was approved by the Ethical and Protocol Review Committee of the College of Health Sciences, University of Ghana.

Inclusion and exclusion criteria and case definition

The inclusion criteria were patients aged 50 years and older with active nAMD, who were treatment naïve or had not received any previous anti-VEGF treatment for at least 3 months prior to initiation of IVZ, and had a minimum follow-up of 6 months. The diagnosis of nAMD was based on clinical features and supportive investigations including colour fundus photograph (CFP), fundus fluorescein angiography (FFA) (Zeiss 450 fundus camera) and SD-OCT (3D OCT-2000, Topcon, Tokyo, Japan). Eyes with active nAMD satisfied the following criteria for inclusion: presence (or recurrence) of intraretinal or subretinal haemorrhage, abnormal retinal thickness particularly with evidence of intraretinal, subretinal, or subpigment epithelial fluid accumulation optimally confirmed by SD-OCT, and new or persistent leakage shown on FFA. Other criteria included choroidal neovascular membrane (CNV) hyperfluorescence on FFA with increase in size in the late phase unless solely due to dry fibrotic membrane with late staining which does not classically increase in size and visual acuity deterioration considered likely to represent CNV activity. A presumptive diagnosis of polypoidal choroidal vasculopathy (PCV) was made if slit lamp biomicroscopy or CFP showed a paucity of drusen, massive subretinal or subretinal pigment epithelium (subRPE) haemorrhage with or without retinal exudates, orange subretinal nodule(s) and recurrent serous or haemorrhagic pigment epithelial detachment (PED) supported by any three of the following SD-OCT B-scan features of: multiple PEDs, highly protruded PED, double-layer hyper-reflective lines, notched PED and rounded subRPE hyporeflective area.17,18 The exclusion criteria included intraocular surgery within 3 months of initial IVZ injection in the study eye, laser photocoagulation or intravitreal corticosteroid or anti-VEGF within 3 months of IVZ, patients with CNV from causes other than nAMD, and myopia ≥−6.0 dioptres.

Demographic and clinical characteristics of patients

The demographic and clinical characteristics of the patients recorded include age, sex, systemic comorbidities, affected eye, presenting complaint, duration of symptoms, type of previous anti-VEGF injection, number of previous anti-VEGF injection and time interval since last injection, diagnosis and status of fellow eye at baseline. Best-corrected visual acuity (BCVA) recorded using a Snellen chart and converted to logMAR values, intraocular pressure (IOP), lens status, and central macular thickness (CMT) at baseline and at 3, 6, and 12 months and the last follow-up visit were recorded. The number of IVZ injections received at 3, 6, and 12 months and at the last follow-up visit were also recorded. The interval between the last injection of IVZ and the last follow-up visit were calculated. The status of the macular and number of recurrences at the last followup visit were recorded. The type of ocular and systemic adverse events occurring during the period were also recorded.

Intravitreal injections

IVZ (1.25 mg/0.05 ml) was given on a monthly basis until the macula was dry (absence of intraretinal and subretinal fluid). Subsequent injections were given on pro re nata (PRN) basis. The criteria for retreatment (recurrence of disease activity) included VA loss of at least one line on the Snellen visual acuity chart with evidence of fluid in the macula, increase in CMT of at least 100 μm or the presence of new macula haemorrhage.

Outcome measures

The primary outcome measure is BCVA at 6 months follow-up. Secondary outcome measures are BCVA at 3 and 12 months and at the last follow-up visit, CMT at 3, 6, and 12 months and at the last follow-up visit, the proportion of eyes that gained at least one, two and three BCVA lines from baseline, number of recurrences and maximum treatment-free interval at the last follow-up visit, and ocular and systemic adverse events.

Statistical analysis

SPSS V.24 (IBM, Chicago, Illinois, USA) was used for statistical analyses. Continuous variables were presented as mean and standard deviation. Categorical variables were compared using chi-square or Fisher’s exact test. Pre- and post-injection changes in BCVA, IOP and CMT were compared using the paired t-test. The frequencies of ocular and systemic adverse events were computed. A p-value <0.05 was considered statistically significant.

Results Demographic and clinical characteristics

Twenty-four eyes of 23 patients (14 females) were included in this study, and 14 eyes had follow-up duration of at least 12 months at the last visit. The mean age ± standard deviation (range) was 67.7±8.8 yrs (50–87 yrs) and the mean duration of follow-up was 11.4±4.0 months (6–16 months). The presenting complaint was blurred vision at presentation in all eyes except two who had metamorphopsia, and the mean duration of visual complaint was 7.6±7.9 months (2 weeks to 24 months). Systemic comorbidities (number) among the patients included in this study were systemic hypertension (11), diabetes mellitus (five), asthma (two) and sickle cell disease (one). Six patients had glaucoma in the affected eye. Five eyes were pseudophakic and 19 phakic. Six eyes had previous anti-VEGF injections prior to IVZ, the mean number of previous antiVEGF injections was 6.5±8.7 (1–24) and these eyes were free of injections for a mean of 9.8±7.7 months (range, 3–20 months) prior to switching to IVZ. The baseline demographic and clinical characteristics of study eyes are summarised in Table I.

Nine (37.5%) of the eyes (five females and four males) with diagnosis of nAMD were presumed to have PCV based on clinical features. Representative cases of PCV are shown in Figures 1 and 2. One patient with presumptive diagnosis of PCV with extensive subretinal haemorrhage had breakthrough vitreous haemorrhage at presentation (Figure 3). The vitreous haemorrhage was observed to clear at 10 months after initiation of IVZ therapy.

Figure 1. Fundus photographs and SD-OCT B-scans of a 66-year-old male presenting with multiple recurrent haemorrhagic pigment epithelial detachments (PEDs). PED notch (green arrow), sharppeaked PEDs (red arrowheads), double layer sign (black arrowheads). Retinal pigment hyperplasia and atrophy (red star) a result of previous laser photocoagulation of haemorrhagic PED. A, E: Presentation with third recurrence of disease activity (large haemorrhagic dome-shaped PED) after 12 bevacizumab and six ranibizumab injections. B, F: Reduction of PED height after additional three bevacizumab injections. C, G: Six months after initiation of ziv-aflibercept 1.25 mg/0.05 ml injection. D, H: Fourth recurrence of disease activity 15 months after initiation of ziv-aflibercept

Figure 2. Fundus photographs (A, C), SD-OCT (B, D) and FFA (E, F) of a 68-year-old male with presumptive diagnosis of PCV PEDS: red arrows, polyp: blue arrows

Figure 3. Fundus photograph, fluorescein angiography and SD-OCT of 50-year-old female with presumed PCV A: Fundus photograph showing extensive subretinal/retinal haemorrhage extending from the disc margin to the fovea; B: SD-OCT showing subretinal haemorrhage (red arrow), PED notch (red arrowhead), thumb-like polyp (blue arrowhead); C, D: fluorescein angiography showing masking of fluorescence (C) and leakage in the late venous phase (D)

A total of 127 injections of IVZ were given over the study period. The mean number of anti-VEGF injections at 3, 6 and 12 months and at the last follow-up visit were 2.6±0.6 (1–3), 3.8±1.2 (1–6), 5.9±2.0 (1–8) and 5.2±2.6 (2–10), respectively. The maximum treatment-free interval was 3.7±2.9 (1–12) months, median 3 months at the last followup visit, and mean number of visits was 8.6±2.9 (4–14) at the last follow-up visit. The mean IOP was 16.1±3.7 (10–25) mmHg at baseline and there was no significant difference in the mean IOP at 3, 6 and 12 months and at the last follow-up visit compared to baseline (Table II).

Visual outcome

Seventy-nine per cent of eyes had visual gain of at least one BCVA line at 6 months post-initiation of IVZ and the visual gain was maintained at 12 months (Table II). Only one (4.1%) eye had a visual decline of more than three Snellen acuity lines at 6 months and at the last follow-up visit due to occurrence of endophthalmitis. The mean baseline BCVA was 1.12±0.7 logMAR and there was significant improvement in BCVA to 0.78±0.6 and 0.79±0.6 respectively, at 3 and 6 months, and at the last visit (0.76±0.6) compared to baseline BCVA (Table II). Although there was improvement in the mean BCVA at 12 months (0.71±0.4) compared to baseline, the difference was not statistically significant.

Anatomic outcome

CMT at baseline was 332.4±138.8 μm and there was significant reduction in CMT at 3, 6 and 12 months and at the last visit compared to baseline (Table II). Intraretinal fluid was present in 14/24 (58.3%) eyes at baseline compared to 4/23 (17.4%) eyes at the last follow-up visit. Subretinal fluid was present in 20/24 (83.3%) eyes at baseline compared to 1/23 (4.3%) at the last visit. Retinal pigment epithelial detachment was present in 20/24 (83.3%) eyes at baseline compared to 6/23 (26.4%) eyes at the last visit (Table II).

At the last follow-up visit, 14 (60.9%), one (4.3%) and one (4.3%) eyes, had one, two and three recurrences of disease activity, respectively. Among the 14 eyes which had a follow-up visit of at least 12 months, nine (64.3%) and two (14.3%) had one and two recurrences of disease activity respectively, at 12 months. One eye with classic CNV and follow-up duration of 15 months had persistent intraretinal fluid attributed to vitreomacular traction syndrome.

Adverse events

One eye in a 77-year-old male with uncontrolled diabetes mellitus developed endophthalmitis in the right eye two days after the fourth injection of IVZ for a peripapillary choroidal neovascularisation (Figure 4). His BCVA prior to initiation of IVZ was 0.32 logMAR and improved to 0.18 logMAR after three injections of IVZ. Visual acuity at presentation with painful loss of vision was hand motion. He had vitreous tap and intravitreal injection of vancomycin 1 mg/0.1 ml, ceftazidime 2 mg /0.1 ml and dexamethasone 0.4 mg/0.1 ml. Culture of vitreous specimen isolated Staphylococcus epidermidis. Visual acuity declined further to perception of light seven days after intravitreal injection of antibiotics, and the eye developed hypotony (IOP = 2 mmHg) associated with choroidal detachment which was observed on B-scan ultrasonography. He subsequently had pars plana lensectomy and pars plana vitrectomy. Fundus examination postoperative showed clear ocular media and round pre-retinal exudates (Figure 4). A presumptive diagnosis of fungal endophthalmitis was made and he was started on oral fluconazole 200 mg daily for seven days and had intravitreal voriconazole 100 mcg/0.1 ml and vancomycin 1 mg/0.1 ml on the seventh day postoperative. He subsequently had an additional six IVZ injections and secondary implantation of posterior chamber intraocular lens. His BCVA at the last follow-up visit was 0.78 logMAR (6/36 Snellen equivalent). No other serious ocular or systemic adverse event was observed in this study.

Figure 4. Fundus images of 77-year-old male with peripapillary choroidal neovascularisation who developed endophthalmitis following fourth injection of IVZ Colour photo, late phase fluorescein angiogram and OCT at presentation (A, B, C, D). E: Anterior segment photograph showing cornea haze, hypopyon (red arrow), and fibrin over pupil; F: SD-OCT image at 1 week after pars plana lensectomy (PPL) and vitrectomy (PPV); G: Fundus photograph 1 week after PPL and PPV showing lens fragments (black arrow) and round pre-retinal lesions. Fundus photograph (H) and SD-OCT B-scan (I) 12 months after onset of endophthalmitis

Discussion

In this study, there was a significant improvement in the visual and anatomic outcome at 3, 6, and 12 months and at the last follow-up visit following IVZ injection for nAMD.

In a prospective non-randomised study of the safety and efficacy of IVZ in 14 eyes with nAMD, de Oliveira Dias et al. reported improvement in BCVA from 0.95±0.41 from baseline to 0.75±0.51 at 52 weeks (p=0.0066).14 Despite the difference of no ‘loading’ of three-monthly injections of IVZ, the VA improvement at 6 and 12 months in this study were similar to that observed by De Oliveira Dias et al. 14 Although the VA outcomes were significant at the primary endpoint, and at other times, the lack of significant difference in VA at 12 months may be due to the small number of patients included in this study. There was significant improvement in the mean CMT in our study at 12 months as observed by De Oliveira Dias et al. 14 Mansour et al. reported on the 3-month outcome of IVZ in a cohort of 30 patients with nAMD.15 They observed improvements in both the CMT and BCVA after receiving monthly IVZ (1.25 mg/0.05 ml) for three consecutive months.15 It was further observed that the treatment-naïve cases had better anatomic response (p=0.008) and improvement in BCVA compared to those who were resistant to bevacizumab or ranibizumab injections (p=0.008).15 Braimah et al. reported on the one-year outcome of IVZ in 16 eyes with nAMD who were non-responsive to bevacizumab or ranibizumab.12 One-third of the eyes had a visual gain of one logMAR line and there was an average reduction of 2.5 injections.12 They concluded that a reduction in the frequency of injections of intravitreal anti-VEGF could result in reduced cost to both patients and the healthcare system.12

The use of IVZ is off-label. Guo et al. assessed the one-year VA response to aflibercept in patients with nAMD using pooled data from clinical trials and observational studies.19 They reported a VA improvement of 7.37 letters at 12 months following use of aflibercept.19 The standard dose of aflibercept is 2 mg/0.05 ml. However, Schmidt-Erfurth et al. have reported that both the 0.5 mg and 2 mg doses of aflibercept achieved comparable visual outcome in the VIEW studies.10 We used 1.25 mg/0.05 ml of IVZ in our study and observed a median difference in VA of −0.16 logMAR (eight letters improvement) in 14 eyes that achieved follow-up of 12 months. Several studies have reported that the 1.25 mg/0.05 ml of IVZ was safe and effective in eyes with retinal vascular diseases.12-15

The safety of IVZ appears similar to other anti-VEGFs.20 Singh et al. reported the occurrence of one case of culture-proven endophthalmitis following 5 914 injections of ziv-aflibercept using pooled data across nine centres.20 Our case of endophthalmitis in this study is the same case reported by Singh et al. 20 The rate of endophthalmitis of 0.78% in this study, although it appears quite high, can be attributed to the small sample size and lower number of injections in this series.

Although indocyanine green angiography (ICGA) is the gold standard for diagnosis, SD-OCT is increasingly becoming a useful imaging modality for the diagnosis of PCV.17,18,21 De Salvo et al. retrospectively compared the SD-OCT and ICGA of 51 eyes of 44 patients who had one or more serous/ haemorrhagic PED due to PCV or occult CNV.17 They reported that the presence of four SD-OCT features (multiple PED, PED notch, sharp PED peak and sub-RPE hyporeflective lumen within hyper-reflective lesions) had high sensitivity and specificity for differentiating PCV from occult CNV with high positive and negative predictive values.17 In a prospective study of 188 eyes by Liu et al., the presence of two out of three SD-OCT features (PED, doublelayer sign, and thumb-like polyps) had 89.4% sensitivity and 85.3% specificity in distinguishing PCV from nAMD.18 In a retrospective study of the CFP, SD-OCT and FFA of 119 eyes with serosanguinous maculopathy (thus PCV, nAMD and central serous chorioretinopathy) Chaikitmongkol et al. reported that combined CFP and SD-OCT provided the highest sensitivity, high specificity and positive predictive value in the diagnosis of PCV.21 We do not have access to ICGA to confirm the diagnosis of PCV in our series. The use of slit lamp biomicroscopy findings, CFP and SD-OCT showed the presence of PCV in 37.5% of our study eyes. The high prevalence of PCV in this series is supported by previous reports of a higher prevalence of PCV in people of African and Asian descent.2,22

The limitations of this study include small sample size, retrospective design, lack of access to ICGA to confirm the diagnosis of PCV and non-uniform followup. We have demonstrated the potential efficacy of 1.25 mg IVZ in an African population despite these limitations. Clinical, CFP and SD-OCT features were very supportive of the diagnosis of PCV despite lack of access to ICGA.

Conclusion

We conclude from this retrospective series that 1.25 mg IVZ administered on a PRN basis in nAMD eyes was associated with significant reduction in CMT at 3, 6 and 12 months and at the last follow-up visit. There was improvement in visual outcomes at 3, 6 and 12 months, and at the last follow-up visit compared to baseline VA. There was one serious adverse event (endophthalmitis) in this study with unfavourable visual outcome. There is the need for a large prospective study on the efficacy of IVZ in nAMD in African populations. There is further need for a study that would categorise the various types of AMD in African populations.

Acknowledgements

The authors wish to thank the staff of the medical records department, treatment room and outpatient clinic of the Eye Centre, Korle-Bu Teaching Hospital, for their support while this study was being conducted. We express our gratitude to participants who voluntarily consented for their images to be included in this study.

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